The interaction of the programmed death receptor ligands 1 and 2 (PDL1/CD274 and PDL2/CD273) on tumor cells with PD-1 receptors on T cells leads to reduced T-cell activation and proliferation, thus enabling tumors to evade immune response (see Figure 1) [42]. The amplification of PDL1 and PDL2 on tumor cells, coded on chromosome 9p24.1, is mediated by PIM serine/threonine kinases on tumor cells via the constitutive activation of the NFkB and JAK-STAT signaling pathways [43].

Anti-PD-1 monoclonal antibody (mAb) therapies reconstitute the immune surveillance of malignant cells, enabling a rapid reduction in Reed-Sternberg cells and PDL1+ inflammatory cells as well as a durable PD-1 blockade that persists even after treatment cessation based on patient samples during and after treatment [44]. A rise in CD4+ T cell receptors, dendritic cells, and mature, highly differentiated NK cells is seen in peripheral blood after anti-PD1 mAb treatment, correlating with earlier and more robust clinical response [44,45,46,47].

PDL-1 expression is a well-defined marker of response to anti-PD-1 mAb across multiple cancer subtypes. In addition to this, 9p24.1 copy number amplification and the expression of major histocompatibility complex class II are associated with improved response to CPI in cHL [48]. In the frontline setting, these biomarkers did not demonstrate an association with early response rates with anti-PD-1 mAb-based therapy [49]. Emerging data on the role of metabolic disorders and patient demographic factors such as sex, age, and gender on effector T cell activity and PD-1 expression suggest that these factors may also contribute to CPI efficacy [50]. The further investigation of these tumoral biomarkers and the effects of extra-tumoral risk factors on TME may help guide treatment decision-making in the future.

Lastly, other immune checkpoints have been identified as potential targets in the TME of cHL, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) [51,52]. The CD68 ligand that binds CTLA-4 is commonly expressed on HRS cells, and this expression persists after treatment with PD-1 blockade. This has therefore served as the rationale for targeting this protein with the monoclonal antibody ipilimumab to overcome anti-PD-1 mAb resistance [51]. Although LAG-3 and TIM-3 are not as frequently expressed on HRS cells, these proteins are commonly seen within the TME surrounding HRS cells [52]. However, ongoing investigation is needed to identify the clinical utility of targeting these alternative immune checkpoints.

For patients with R/R disease after multiple lines of therapy including ASCT +/− BV, anti-PD-1 mAb monotherapy has an overall response rate (ORR) of ~70% with a median PFS of 14–15 months. Although only 20–30% of responders have CR in this setting, those who do achieve CR have a prolonged remission with a median duration of response (mDOR) of 37 months with nivolumab; additionally, mDOR was not reached with pembrolizumab at 5 year follow-up [23,53]. In a study of anti-PD-1 mAb tislelizumab in patients with relapse after ASCT or 2 systemic regimens in a Chinese population, 67% of patients achieved CR, and ~50% of patients had ongoing response at 30 month follow-up, confirming the correlation of depth of response to duration of response with this class of agents [27]. Novel combination regimens of immunotherapy combined with other targeted therapies have deepened response rates in the multiple-relapse setting. The combinations of BV with the checkpoint inhibitors nivolumab and ipilimumab achieved CRs of 61% and 57%, respectively. Although the combination of all three agents achieved the highest CR of 73%, the inclusion of ipilimumab resulted in higher toxicity than BV + Nivo in this phase I/II study. The rates of grade 3–4 adverse events were reported at 43% and 50%, respectively, in the BV-Ipi and triplet combination arms but only 16% in the BV-Nivo group. [31]. Therefore, anti-PD-1 mAb based therapies are preferred.

In early clinical investigation, the addition of hypomethylating agent to anti-PD-1 mAb improved CR from 32 to 71% in patients with R/R cHL to at least 2 prior lines of therapy, with 100% of patients still responding to combination therapy at 6 month follow-up. Investigational regimens evaluating nivolumab in combination with JAK2 inhibitor, and BTK inhibitor are also underway. Additionally, retreatment with anti PD-1 mAb has been described in a small number of patients with multiply relapsed disease, demonstrating ORRs of 70–100% and CRs of 33–73% [54,55,56,57]. Phase II investigation of combination BV + Nivo in patients with prior treatment of either agent is underway and may provide more insight into the roles of sequencing and retreatment as these agents are introduced to patients in earlier lines of therapy.

Treatment with standard chemotherapy options in first relapse followed by ASCT leads to long-term cure in only half of patients, with reported 6 year event-free survival and overall survival (OS) of 45% and 55%, respectively [58]. Standard cytotoxic chemotherapy salvage achieved an ORR of ~70–90% and a CR of ~20–30% [59,60,61,62,63]. In patients who fail to respond to initial salvage chemotherapy, the outcomes after ASCT are particularly dismal. At 10 year follow-up, the PFS and OS are only 7–23% and 11–17%, respectively [60,61] Achieving complete metabolic response (CMR) to salvage therapy prior to ASCT is associated with superior outcomes and has served as a rationale for incorporating targeted therapies into first salvage lines of therapy. While the addition of BV into first-line salvage regimens has improved CR to 70–80% [62,64,65,66], single-agent BV induces CRs of only 27–43% when assessed as monotherapy or as part of PET-adapted bridging therapy ASCT [67,68].

On the other hand, the investigation of anti-PD-1 mAb in the first relapse in several phase II studies has demonstrated increased depth of response both as a single agent and as combination therapy  [33,34,35]. Combination BV and Nivo demonstrated ORR of 82–85% and CR of 59–67% [32,69,70] At 3 year follow-up after combination achieved a PFS of 77%, and in patients who responded to induction and proceeded to ASCT, PFS improved to 91% [33]. In a small phase II PET-adapted study evaluating nivolumab monotherapy followed by escalation to nivolumab with ifosfamide, carboplatin, and etoposide (ICE) in patients with positive interim PET scans, 71% of patients achieved CR to the single agent nivolumab and were eligible to proceed directly to ASCT, sparing 26 of the total 42 evaluable patients from requiring cytotoxic treatments prior to ASCT. A total of 9 of the 42 patients required escalation of their treatment to N-ICE, and of these, 89% achieved CR [35]. This approach demonstrated overall 2 year PFS and OS of 72% and 95%, respectively [35]. Larger studies are underway to evaluate nivolumab monotherapy as salvage prior to ASCT.

Other small studies evaluating combination of immunotherapy with standard regimens as bridge to ASCT, including pembrolizumab combined with ICE or gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), showed similarly high CR rates of 86–95% [36]. The active investigation of other anti-PD-1 mAb combination regimens via a PET-adapted approach using anti-PD1 mAb with GVD are underway to assess efficacy with less toxic or chemotherapy-sparing therapies.

Historical data in patients with R/R disease within 1 year of frontline therapy who are treated with standard salvage chemotherapy followed by ASCT demonstrated a 10 year freedom from second failure (FF2F) and OS of 34 and 43%, respectively [9]. The incorporation of CPI has significantly improved outcomes in this population. In a subgroup analysis of R/R patients treated with pembrolizumab, patients with primary refractory disease achieved a CR of 35% with mDOR of 17 months at a median of 28 month follow-up, achieving 2 year PFS and OS of 32% and 94%, respectively. In a phase II study of pembrolizumab with chemotherapy (GVD) as initial salvage therapy as a bridge to ASCT, 79% of patients had either primary refractory disease or relapse within 1 year. All patients responded to this combination treatment with a remarkable CR of 95%, and 36 of the 39 patients enrolled proceeded to ASCT. All remained in remission at 13.5 month follow-up [34].

Lastly, CPI has also been explored as consolidation therapy after ASCT similar to BV, as investigated in the phase III ATHERA study [15,37]. In the ATHERA study, high-risk patients, defined as primary refractory or relapse/progression of disease within 12 months of frontline therapy or extra-nodal involvement at relapse, were included. Extended follow-up of BV maintenance demonstrated a 5-year PFS of 59% vs 41% with placebo [37]. Phase II evaluation of pembrolizumab after ASCT demonstrated an estimated 18 month PFS of 82% overall, and among patients in the subgroup who met the criteria for high-risk disease per the ATHERA protocol, PFS was 85% [15,37].

In the absence of long-term follow-up and head-to-head comparison, the PFS with post-ASCT consolidative pembrolizumab compares favorably with that of BV. However, as BV has moved to the upfront setting as the standard of care for advanced-stage cHL and nivolumab is being used in earlier lines of therapy, the role of maintenance BV or anti-PD-1 mAb is less clear. Ongoing phase II investigation of the combination of BV and nivolumab in patients with relapse who previously received either agent may provide insight into the roles of sequencing and retreatment with these agents as consolidation post ASCT.